NLRP3-dependent IL-1β production by FcγR-mediated Syk kinase signaling confers protective immunity in Francisella tularensis vaccination (VAC7P.966)
| Autor: | Sivakumar Periasamy, Ellen Duffy, Jonathan Harton |
|---|---|
| Rok vydání: | 2014 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 192:141.11-141.11 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.192.supp.141.11 |
| Popis: | Pneumonic tularemia is a fatal disease caused by Francisella tularensis (Ft), a category ‘A’ biothreat agent with no FDA approved vaccine. Previous studies have shown that inactivated-Ft (iFt) complexed with anti-Ft LPS mAb (iFt-mAb) elicits protective immunity against lethal Ft challenge. Other vaccine studies have also shown that IL-1β and NLRP3 play a role in adaptive immunity. The AIM2 inflammasome is critical for innate immunity to Ft, but NLRP3 appears to be unnecessary. We investigated the role of inflammsomes in immune responses to iFt-mAb and found that NLRP3 is essential in this vaccine strategy. An iFt-mAb vaccination completely failed to protect IL-1RKO and NLRP3KO mice against lethal Ft challenge compared to Wt mice. Importantly, Ft-specific antibodies were significantly lower in both KO mice than Wt mice after vaccination and challenge. NLRP3-deficient mBMDM or THP-1 cells produced significantly less IL-1β compared to WT cells after iFt-mAb treatment. To probe the mechanism by which iFt-mAb activates NLRP3 and IL-1β, the role of FcγR and TLR2 signals were explored. Internalization of iFt-mAb and activation of NLRP3 were FcγR-dependent, while NLRP3-dependent IL-1β production required TLR2 and FcγR-signaling through Syk kinase. Our results highlight the role of IL-1β and NLRP3 in successful iFt-mAb vaccination that elicits better antibody and cellular responses. Specifically, FcγR signaling is required for NLRP3 inflammasome activation in this vaccine strategy. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|